Embryonic stem cells (ESCs are pluripotent cells derived from the inner cell mass of the blastocyst-stage embryo. They can be used as a model system to study the molecular basis of pluripotency and fate-specification during early mammalian development. They can also be used to derive various types of cells for disease modeling, drug discovery, and the development of cell-based therapies. However, the success of these studies and applications critically depends on the understanding of the mechanisms that control ESC self-renewal and differentiation. To systematically study ESC self-renewal, we have previously carried out a genome-wide siRNA screen in mouse ESCs and successfully identified a list of novel genes that are important self-renewal. We are currently investigating the function of several of these novel genes in ESCs with biochemical, genetic, and genomic approaches. For example, we have shown that three of the Ccr4-Not family genes form a complex in ESCs and are required for both mouse and human ES cell self-renewal by inhibiting differentiation into extraembryonic lineages. The Fip1 gene regulates mRNA alternative polyadenylation to promote ESC self-renewal. The THO protein complex regulates pluripotency gene mRNA export and controls both ESC self-renewal and somatic cell reprogramming. The INO80 protein complex facilitates pluripotency gene activation in embryonic stem cell self-renewal, reprogramming, and blastocyst development. We are now using biochemical and genetic experiments to further study the function of these genes in ESCs, induced pluripotent stem cells, and mouse embryogenesis. Using similar approaches, we are also investigating the roles of other novel self-renewal regulators. Besides the characterization of the above self-renewal factors, we are collaborating with the NTP and use chemical genetic approaches to probe and identify environmental chemicals that may affect human development. We are using human ESCs as an in vitro model to study the developmental toxicity of the environmental compounds, and we hope to gain a better understanding on the impact of environmental factors on human embryogenesis and embryonic development. Finally, we will continue to use functional genetic approaches to study the guided-differentiation of ESCs and the self-renewal of other types of stem cells. We also plan to study the expression and the roles of stem cell genes in cancer. We hope that our studies will facilitate the development of stem cell therapies, and identify novel therapeutic targets or diagnostic markers for cancer treatment. In summary, we use ESCs as a model system to investigate the mechanism of stem cell self-renewal and differentiation. Our studies will lead to a better understanding of developmental biology, and it will contribute to the advance of the therapeutic use of stem cells in regenerative medicine, as well as the use of stem cells in the study of environmental sciences.